1. Field
The present invention relates to a novel method of screening an agent for preventing or treating cancer using glycyl-tRNA synthetase (GRS) and cadherin. More is particularly, it relates to a method of screening a test agent which modulates the binding level of GRS or their fragment with CDH.
2. Discussion of the Background
As ancient proteins that arose as part of the development of the genetic code, aminoacyl tRNA synthetases (AARSs) are essential components of the translation apparatus. The 20 enzymes, one for each amino acid, catalyze the attachment of each amino acid to its cognate tRNA in the cytoplasm, where the charged tRNAs are then used for ribosomal protein synthesis. Surprisingly, ex-translational functions have been discovered for many tRNA synthetases, including gene regulation in E. coli, RNA splicing in mitochondria of N. crassa, (Kemper et al., 1992. Mol. Cell. Biol. 12, 499-511) and a diverse variety of functions in vertebrates that include among others regulation of inflammatory responses and of angiogenesis (Park et al., 2005. Trends. Biochem. Sci. 30, 569-574). These expanded functions are associated with the accretive additions of specialized motifs and domains such as internal short sequence motifs and appended GST, leucine zipper, and helix-turn-helix domains (Guo et al., 2010. FEBS Lett. 584, 434-442). The specialized motif and domain additions facilitate new protein-protein interactions that confer novel functions. Some of the many disease connections to AARSs, and to proteins that are part of the multi-tRNA synthetase complex in mammalian cells, is thought to result from disruptions to, or alterations of, their ex-translational functions (Park et al., 2008; Sampath et al., 2004). Indeed, there are dominant Charcot-Marie-Tooth disease-causing mutations in tyrosyl- and glycyl-tRNA synthetases that do not disrupt aminoacylation activity (Jordanova et al., 2006. Nat. Genet. 38, 197-202; Nangle et al., 2007. Proc. Natl. Acad. Sci. USA 104, 11239-11244).
Also surprising for essential components of the translation apparatus was the observation that specific fragments (produced by alternative splicing or natural proteolysis) of tyrosyl- and tryptophanyl-tRNA synthetases (YRS and WRS) bind to and signal through extracellular receptors, including CXCR1 and 2 on PMN cells (YRS) (Wakasugi and Schimmel, 1999. Science 284, 147-151) and VE-cadherin on endothelial cells (WRS). These two synthetases are secreted from mammalian cells under specific conditions that potentiate their ex-translational functions (Wakasugi et al., 2002. Proc. Natl. Acad. Sci. USA 99, 173-177; Yang et al., 2007. Structure 15, 793-805). Collectively, these observations raised the possibility that one way to discover ex-translational functions of tRNA synthetases might be by annotating those that were present in a physiological setting that did not carry out translation (Park et al., 2008, Proc. Natl. Acad. Sci. USA 105, 11043-11049; Sampath et al., 2004. Cell 119, 195-208). This consideration led us to examine the presence of specific synthetases in human serum.